1. Field of the Invention
The present invention relates to ocular hypotensive lipids. More particularly the present invention relates to PGF2xcex1 1-ethanolamide and related compounds, and to pharmaceutical compositions containing these compounds, as well as methods for using the compounds to lower intraocular pressure in a mammal.
2. Brief Description of the Prior Art
The prior art is well aware of numerous ocular hypotensive agents which are used to treat various ocular hypertensive conditions, including primary and secondary glaucoma which represent a serious human health problem. Drugs used for treating ocular hypertension (glaucoma) include xcex2-adrenoreceptor antagonists, and various prostaglandins. There is a substantial volume of scientific and patent literature pertaining to prostaglandins and to their use in the treatment of ocular hypertension. See for example Bito L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton. Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune and Stratton, 1984, pp. 477-505.
U.S. Pat. No. 5,288,754 includes further citations to specific prior art directed to prostaglandins and related derivatives which are active as agents for reducing intraocular pressure in a mammal. U.S. Pat. No. 5,288,754 itself, describes xe2x80x9cPolar C-1 Esters of Prostaglandinsxe2x80x9d, including C-1 amides and C-1 substituted amides of the carboxylic acid compound known as PGF2xcex1. Additional prostaglandin derivatives related to PGF2xcex1 which have emerged in prior art research conducted in the research facilities of the corporate assignee of the present application and which show strong intraocular hypotensive activity, are shown below by formula and are identified by arbitrary numbers as xe2x80x9cprior art compound no. 1xe2x80x9d and xe2x80x9cprior art compound no. 2xe2x80x9d. Prior art compound no. 1 is described in U.S. Pat. Nos. 5,352,708; 5,607,978 and 5,688,819, and prior art compound no. 2 is described in U.S. Pat. No. 5,545,665. 
The vast majority of ocular hypotensive agents which have a prostaglandin (or closely) related structure act through known xe2x80x9cprostglandinxe2x80x9d receptors. Particularly, the compound PGF2xcex1 is known to exert its ocular hypotensive action through the receptor known as FP. By xe2x80x9cFP receptorxe2x80x9d is meant a human prostaglandin receptor as disclosed in Abramovitz et al., J. Biol. Chem. 269:2632 (1994), hereby incorporated by reference herein. The structure of PGF2xcex1, including the numbering customarily used in the nomenclature of prostaglandin and related compounds, is shown below. 
The present invention is directed to a class of compounds related to PGF2xcex1 1-ethanolamide, which suprisingly have been discovered, together with the prior art compound nos. 1 and 2, as agents having strong ocular hypotensive activity, but which do no exert their ocular hypotensive effects through the FP receptor, nor through any hitherto recognized prostaglandin receptor, such as DP, EP, EP2, EP3, EP4, FP, IP and TP.
The present invention is directed to compounds of Formula 1 wherein the dashed lines represent absence of a bond, or a bond with the proviso that there are no two adjacent double bonds in the formula;
the wavy line attachments represent either alpha (xcex1, down) or beta (xcex2, up) configuration, where the wavy lines are attached to a double bond they represent either Z (cis) or E (trans) configuration;
the hatched lines indicate alpha (xcex1) configuration and solid triangles indicate beta (xcex2) configuration;
m is an integer having the values of 0 to 5;
n is an integer having the values 1-6, with the proviso that the compound represented by the formula is not PGF2xcex1 1-ethanolamide;
q and r each independently are integers having the value of 0 to 6;
X is CH2, O or S with the proviso that when X is O or S then the dashed line adjacent to X represents absence of a bond;
R is CH3, phenyl, furyl, thienyl, cycloalkyl of 3 to 8 carbons, or phenyl furyl or thienyl itself substituted with one or two substituents selected from the group consisting of F, Cl, Br, alkyl of 1 to 6 carbons, NO2, CN, COOH and COOalkyl where alkyl has 1 to 6 carbons;
R1, R2, R3, and R4 each independently represent H, a straight or branch-chained alkanoyl group having 1 to 6 carbons, benzoyl or lower alkyl of 1 to 6 carbons;
R5 is H or straight or branch-chained alkyl group having 1 to 6 carbons, and
R6 is H or straight or branch-chained alkyl of 1 to 4 carbons or a pharmaceutically acceptable salt of said compound, and said compounds being active to lower intraocular pressure in the eye of a mammal but do not exert their ocular hypotensive activity through the FP prostaglandin receptor, nor through any hitherto recognized prostaglandin receptor. 
The present invention is also directed to isolated substantially pure PGF2xcex1 1-ethanolamide, which has surprisingly been discovered to be present in certain biological systems as a naturally occurring substance. Further, the present invention is directed to pharmaceutical compositions containing as an active ingredient PGF2xcex1 1-ethanolamide and/or one or more of the compounds in accordance with Formula 1, and to the process of treating a mammal, including a human, in need of such treatment with an effective amount of a pharmaceutical composition containing as active ingredient PGF2xcex1 1-ethanolamide and/or one or more of the compounds in accordance with Formula 1, for the purpose of lowering intraocular pressure.